PROJECT ABSTRACT The continued dismal outcomes for pancreatic cancer patients reveal our failure to understand molecular mechanisms critical to tumor progression and survival. Our group and others identified the RON tyrosine kinase receptor as an overexpressed protein and potential novel therapeutic target in pancreatic cancer. The working hypothesis of our laboratory is that RON receptor signaling is a potent promoter of invasive growth and survival in human pancreatic cancer that represents a potentially valuable therapeutic target. In support of this idea, we have recently shown that RON receptor downregulation can sensitize pancreatic cancer cells to gemcitabine in vivo. The relevance of RON to pancreatic cancer has also been borne out by recent publications documenting it as a commonly overexpressed protein in pancreatic cancer that may mediate cell survival in the setting of KRAS oncogene addiction. Our own preliminary work suggests that in the mouse, RON overexpression alone can mediate pancreatic carcinogenesis and that it may accelerate carcinogenesis in the setting of oncogenic Kras. Despite these findings, major gaps in our understanding of RON receptor biology and its role in pancreatic carcinogenesis remain. The goals of this application are; 1) to directly test the hypothesis that RON signaling promotes progression of pancreatic intraepithelial neoplasia to pancreatic cancer, 2) to investigate mechanisms of RON ligand dependent and ligand independent activation in pancreatic cancer and, 3) to test the effects of a novel RON monoclonal antibody on the orthotopic growth of patient-derived pancreatic cancer xenografts in order to identify biomarkers associated with activated RON signaling and oncogene addiction. The findings from these studies will enhance our understanding of RON biology and thereby serve to inform the development and further testing of RON-directed therapies in pancreatic cancer.